Cancer-Linked Colgate Total Ingredient Suggests FDA Flaws

Newly released documents that supported the FDA's 1997 approval of Colgate Total toothpaste include indications that its active ingredient, triclosan, may disrupt hormone functions, say three scientists who reviewed the pages. Total's maker, Colgate-Palmolive, says the FDA's approval and annual product-safety updates establish that triclosan is safe and effective in toothpaste. Photographer: Susana Gonzalez/Bloomberg

Aug. 11 (Bloomberg) -- The chemical triclosan has been
linked to cancer-cell growth and disrupted development in
animals. Regulators are reviewing whether it’s safe to put in
soap, cutting boards and toys. Consumer companies are phasing it
out. Minnesota voted in May to ban it in many products.

At the same time, millions of Americans are putting it in
their mouths every day, by way of a top-selling toothpaste that
uses the antibacterial chemical to head off gum disease --
Colgate-Palmolive Co.’s Total.

Total is safe, Colgate says, citing the rigorous Food and
Drug Administration process that led to the toothpaste’s 1997
approval as an over-the-counter drug. A closer look at that
application process, however, reveals that some of the
scientific findings Colgate put forward to establish triclosan’s
safety in toothpaste weren’t black and white -- and weren’t,
until this year, available to the public.

Colgate’s Total application included 35 pages summarizing
toxicology studies on triclosan, which the FDA withheld from
view. The agency released the pages earlier this year in
response to a lawsuit over a Freedom of Information Act request.
Later, following inquiries from Bloomberg News, the FDA put the
pages on its website.

The pages show how even with one of the U.S.’s most
stringent regulatory processes -- FDA approval of a new drug --
the government relies on company-backed science to show products
are safe and effective. The recently released pages, taken
alongside new research on triclosan, raise questions about
whether the agency did appropriate due diligence in approving
Total 17 years ago, and whether its approval should stand in
light of new research, said three scientists who reviewed the
pages at Bloomberg News’s request.

Rodent Bones

Among the pages were studies showing fetal bone
malformations in mice and rats. Colgate said the findings
weren’t relevant. Viewed through the prism of today’s science,
such malformations look more like a signal that triclosan is
disrupting the endocrine system and throwing off hormonal
functioning, according to the three scientists.

Colgate’s application materials also show that the FDA
asked questions about the thoroughness of cancer studies, which
are partly addressed in recently released documents.

Some questions about triclosan’s potential impact on people
are, by nature, unanswerable. Humans are exposed to dozens of
chemicals that may interact in the body, making it almost
impossible to link one substance to one disease, said Thomas
Zoeller, a biology professor at the University of Massachusetts
Amherst, who specializes in how chemicals affect the endocrine
system.

‘Huge Risk’

“We have created a system where we are testing these
chemicals out on the human population. I love the idea they are
all safe,” Zoeller said. “But when we have studies on animals
that suggest otherwise, I think we’re taking a huge risk.”

New York-based Colgate isn’t accused of wrongdoing, and the
35 pages don’t prove triclosan is harmful. It was the FDA’s
decision to keep the documents off of its website, Colgate said.

The FDA followed standard procedure by redacting
information that had come from a third party, said spokeswoman
Andrea Fischer. Some studies were done in the labs of Ciba-Geigy, the first triclosan maker and a predecessor to its
current primary maker, BASF SE, according to the documents. The
pages didn’t denote which studies were done by an outside party,
or who the party was. Fischer declined to identify them.

Fights Gingivitis

Colgate said Total’s effectiveness and safety are supported
by more than 80 clinical studies involving 19,000 people, and
that it gave the FDA 98 volumes, numbering hundreds of pages
each, in support of Total. Colgate submits annual reports to the
FDA reviewing new science and safety findings, said Colgate
spokesman Thomas DiPiazza.

“In the nearly 18 years that Colgate Total has been on the
market in the U.S., there has been no signal of a safety issue
from adverse-event reports,” DiPiazza said. Colgate also
pointed to an independent 2013 review by the Cochrane Oral
Health Group, a network of doctors, researchers and health
advocates, which found no evidence of harmful effects associated
with using Colgate Total.

Total has an important health benefit because it fights
plaque and gingivitis, DiPiazza said. Gingivitis can progress to
periodontal disease, which affects almost half of Americans 30
and over, according to a 2012 study by the Centers for Disease
Control and Prevention.

Soap Review

The FDA reviews all new safety information on ingredients
to determine whether a reassessment is necessary, said Jeff
Ventura, a spokesman. The agency is revisiting triclosan in hand
soaps though not in Total, said Sandra Kweder, deputy director
of the agency’s Office of New Drugs. That’s because while
triclosan hasn’t been proven superior to soap and water at
washing hands, she said, its benefit as an active ingredient in
toothpaste was made clear through its FDA approval process.

Colgate removed triclosan from its Softsoap liquid
handsoaps and Palmolive antibacterial dish liquid in 2011,
citing changing consumer preferences and superior formulations.
It said it has no plans to reformulate Total, which is the only
triclosan toothpaste approved for U.S. sale.

This article is based on interviews with Colgate, former
and current FDA staff and oral biology experts, transcripts of
FDA meetings, as well as on the 35 pages, which the FDA shared
in January with the Natural Resources Defense Council, a public-health advocate that sued for them. The scientists who examined
the pages included Zoeller, a second university-affiliated
endocrine specialist, and an environmental toxicologist
affiliated with the Environmental Working Group, a public health
advocacy.

Pet-Food Dispensers

Of the more than 84,000 chemicals sold in the U.S., few are
attracting more scrutiny than triclosan. Used for decades in
handsoaps, it is now part of almost 200 products including rugs
and pet-food dispensers. Companies including Johnson & Johnson
and Procter & Gamble Co. have vowed to remove it from their
lineups. In May, Avon Products Inc. announced its plans to go
triclosan-free.

Those moves are coming in part as consumers, armed with
toxicity ranking systems such as the Environmental Working
Group’s Skin Deep Database, have turned away from chemicals
including Bisphenol A and phthalates, even in the absence of
firm scientific or regulatory conclusions.

Wariness is mounting as factors from environment to diet
are blamed for a global rise in endocrine-related diseases.
Breast, ovarian, prostate and testicular cancer rates have
increased over the past 40 to 50 years, according to a 2012
report from the World Health Organization and the United Nations
Environment Programme. A rise in preterm and low birthweight
babies, early breast development in girls and undescended
testicles in boys may be linked to endocrine-disrupting
chemicals, the report says.

Regular Exposure

Zoeller, the endocrine specialist, said that while an
estimated 800 to 1,000 chemicals are believed to disrupt the
endocrine system, triclosan is one of about 10 to which people
are regularly exposed. “We may not have to change very much to
have a big impact,” he said.

Total, the No. 3 selling brand in the U.S., lost 2 percent
of its market share last year, with $189.8 million in sales for
the year that ended on Jan. 26, according to market research
firm Mintel Group Ltd. Colgate’s Tom’s of Maine line grew 14
percent, to $38.9 million, suggesting shoppers are gravitating
toward more natural options, the report said.

Procter & Gamble, which makes Crest 3D White and Crest Pro-Health -- the top two U.S. toothpastes according to Mintel --
has sought to capitalize. A Google search for “triclosan” and
“toothpaste” brings up an advertisement linked to a Procter &
Gamble site touting Crest products as “100% triclosan free.”

Triclosan-Free

P&G’s oral-care products have been triclosan-free in the
U.S. and several other markets “for a number of years,” said
Kristopher Parlett, a spokesman for the Cincinnati-based
company. P&G doesn’t produce or market triclosan-containing oral
care products anywhere, he added.

GlaxoSmithKline Plc, which once had triclosan in some
Aquafresh and Sensodyne toothpastes, has reformulated all of its
oral care products that previously contained it, said
spokeswoman Joanmarie Goddard. She couldn’t say what year they
had been reformulated or whether triclosan versions had been
sold in the U.S. The decision was a response to consumer concern
that triclosan across a range of products “may have a negative
environmental impact in the future,” she said.

Hand Scrubs

From its beginnings as an ingredient in surgical hand
scrubs, triclosan -- also identified as 5-Chloro-2-(2,4-dichlorophenoxy)phenol -- has grown to a $100 million a year
chemical globally, according to statistics from the Kline Group.
BASF, based in Ludwigshafen, Germany, sells it under the trade
names Irgasan and Irgacare. India-based Kumar Organic Products
Ltd. and Vivimed Labs Ltd. also make it.

BASF says that 40 years of global studies and publications
prove triclosan’s efficacy in oral care and cosmetic products,
as well as in hand disinfectants and other health-care
applications, according to Thomas Nonnast, a spokesman. Klaus
Nussbaum, a spokesman for Kumar, said studies have established
triclosan’s safety. Vivimed didn’t respond to requests for
comment.

While company-sponsored safety tests on triclosan that
would become part of Colgate’s FDA application for Total began
as early as 1968, U.S. agencies have yet to comprehensively
review it for other uses.

Safety Tests

In 1974, the FDA proposed issuing a so-called monograph
that would determine whether antibacterial ingredients such as
triclosan were considered safe and effective for hand soaps. Two
years later, the U.S. Toxic Substances Control Act of 1976,
which aimed to comprehensively regulate chemicals, grandfathered
in existing substances with no safety testing.

The law gave the EPA -- which oversees triclosan’s use in
durable goods including fabrics and sealants -- the power to
restrict or test substances. It excluded food, drugs and
cosmetics, which fall under the FDA’s mandate. The FDA, four
decades after its first promise, has yet to issue a ruling on
whether triclosan is safe or effective in soaps.

In the meantime, triclosan made its way into toothpaste.

Colgate spent 10 years and $38 million developing Colgate
Total, according to Mintel. Introduced in 1992, it was marketed
in almost 100 countries before gaining U.S. approval, according
to transcripts of FDA meetings.

Colgate's Application

Colgate applied to the U.S. starting in 1992, according to
FDA records, before gaining the FDA’s blessing on July 11, 1997.
In a statement at the time, Colgate called Total “the most
significant advancement in home dental care since the
introduction of fluoride.”

In the early 2000’s, Caren Helbing, a professor at the
University of Victoria in Canada, noticed the SARS outbreak in
China had led to a germ-killing frenzy. Seeing triclosan listed
as an active ingredient in many antibacterial products, she
looked up its chemical structure. It was similar to both thyroid
hormones and to polychlorinated biphenyls, or PCBs, she said.
Such a structure, she and other scientists have said, allow the
chemicals to become active on hormone receptors.

Helbing, who has a Ph.D. in biochemistry and microbiology,
found that tadpoles exposed to triclosan developed into smaller
froglets and had malformed legs -- results that she and other
scientists published in the peer-reviewed Aquatic Toxicology
journal in 2006.

Thyroid Function

Other studies found no such links between the chemical and
hormone function. A 2011 paper published in Science of the Total
Environment found that over four years, the use of triclosan
toothpaste had no detectable effect on thyroid function in
humans. Three of that study’s five authors received a grant from
Colgate. One, Greg Seymour, a professor at the School of
Medicine at the University of Queensland, said Colgate requested
the analysis of thyroid hormones after it granted them money for
a separate study on gingivitis. Colgate had no input on data
collection or analysis, he said.

The Cochrane paper, which Colgate cited in its favor, comes
to a more complex conclusion. The review of more than 30 studies
published from 1990 to 2012 found “moderate quality evidence”
that Total is more effective than other toothpastes at fighting
gum bleeding and inflammation. On the topic of safety, authors
Philip Riley and Thomas Lamont, speaking about the review in a
podcast, said the studies didn’t cover enough years to allow
them to investigate any long-term ill effects.

Long-Term Exposure

“What I would be concerned about is the amount people are
exposed to over time,” said William Bowen, a professor emeritus
at the University of Rochester Medical Center, who specializes
in oral biology and also served on a subcommittee at the FDA
that evaluated dental products in the 1990s.

Meanwhile, triclosan is showing up in humans and the
environment. It was found in the urine of 75 percent of 2,517
Americans tested, including children, according to a 2003 study
by the Centers for Disease Control and Prevention. It and a
related chemical, triclocarban, were detected in 90 percent of
surface water samples from the Great Lakes and in many fish
species, according to a July 2014 study by the Canadian
Environmental Law Association.

Scientific studies that have raised health concerns include
one 2012 study linking triclosan to reduced fertility in mice,
and another that year suggesting it could impair muscle
function. A study last year linked it to lowered sperm
production and changed sperm shape in rats. Triclosan’s core
credentials have also come under scrutiny: While some studies
have supported its benefit in killing bacteria, others have
found it no more effective than soap and water -- and in some
cases suggested it could support growth of bacteria including
the type that causes staph infections.

EU Ban

In 2010, the European Union banned triclosan in materials
that come into contact with food. Three years later, the EPA,
which reviewed the chemical in 2008, began another review, 10
years earlier than planned. It cited the “rapidly developing
scientific database” on the chemical, which includes studies on
thyroid effects, according to its website.

Amid these debates, the Natural Resources Defense Council
turned its attention to one of triclosan’s main regulators. In
2013, it sued the FDA for the toxicology data the agency had
relied on in approving Colgate Total. In January, the FDA handed
the NRDC the 35 pages and later put them online along with a
previously unreleased cancer study and other information.

The pages included a summary of a 1992 study showing that
pregnant mice receiving higher doses of triclosan had lower-weight fetuses and increased incidence of irregular bone
formation in their skulls and paw bones. Five of the 120 mice
delivered prematurely. A study on pregnant rats the same year
found that at higher doses, rat litters had increased incidence
of delayed bone formation in areas including the skull,
vertebrae and pelvis.

The application dismissed both results -- saying the
premature births weren’t dose related and were therefore
“incidental.” The bone-formation issues were due to toxic
effects on the mother, not the fetus, the summary said.

Not Enough Detail

The summaries didn’t provide enough detail to justify those
dismissals, according to the scientists reviewing them.

“Wow. They kept that private?” said Zoeller of the
University of Massachusetts. “The distinction between maternal
and fetal toxicity is an excuse to do nothing. And it’s not
scientifically justifiable.”

Such results could have served as clues for later
scientists if they had been made public, said the third
reviewer, Johanna Congleton, a scientist at the EWG who has a
PhD in Environmental Toxicology from Cornell University.

Amplified Effect

Since Total’s approval, researchers have gained new
insights into chemicals that disrupt the endocrine system. The
Total studies focused on whether triclosan had an amplified
effect as exposure levels rose -- a model consistent with a
longstanding belief that the bigger the dose, the greater the
poison.

Newer science has shown that even small doses of certain
chemicals can significantly affect hormone functions, if they
are delivered at the wrong moment -- and that rising doses may
cause new unpredictable effects, rather than a rising incidence
of the same issue. Some of the data Colgate dismissed in the
non-public pages are “almost a hallmark of endocrine
disruption,” said Helbing, who conducted the study on frogs.

The effects Helbing had documented -- smaller froglets and
malformed legs -- could be seen with doses equivalent to 1/10 of
what a person would use in squeezing a pea-sized amount of Total
onto a toothbrush twice a day, Helbing said.

The 35 pages of recently released documents also include a
cancer study in which triclosan was fed to rats for as long as
two years. FDA reviewers deemed the study inadequate, according
to the recently released document, and called for another.

Industry Alliance

Shortly after, in February 1996, an FDA dental-products
panel said the agency was working closely on a new cancer study
with the Triclosan Industry Alliance -- a trade group whose
members, according to documents on the FDA’s website, included
Colgate, Procter & Gamble and Ciba Specialty Chemicals. Colgate
said it believes the alliance no longer exists.

According to the minutes of the meeting obtained through a
Freedom of Information Act request, the study was expected in 18
months. Total was approved 17 months later.

An industry group’s study was submitted to the FDA in 1999,
said Colgate’s DiPiazza. Both Colgate and the FDA declined to
make that study available.

Carcinogenicity Concerns

The FDA, in response to a Bloomberg News inquiry, said the
agency’s concerns about carcinogenicity had been resolved by a
cancer study that was submitted in January 1997. The study,
which the FDA put on its website following a Bloomberg News
inquiry, “supports the FDA’s conclusion that triclosan does not
pose a cancer risk for humans,” DiPiazza said.

David Kessler, a former commissioner of the FDA from 1990
to 1997, just prior to when Colgate Total was approved, said he
couldn’t comment on the thoroughness of the agency’s review.
Typically, he said, only confidential commercial information is
redacted from public documents. It’s the manufacturer’s
responsibility, he said, to assure its product is safe and that
relevant information is made public.

“The real question is did Colgate do a good job,” Kessler
said.

Colgate continues to reference its FDA bona fides. This
spring, Minnesota became the first state to pass a triclosan
ban. Effective 2017, the state will prohibit the sale of
triclosan-based cleaning products for the hands and body --
except those with FDA approval, such as Total.

Colgate Lobbied

“Colgate came in and lobbied, and said it’s a good
product,” said John Marty, a state senator who sponsored the
bill.

The FDA, meanwhile, has vowed to deliver the monograph
covering triclosan in handsoaps -- the one it promised for the
first time four decades ago -- by 2016.

As part of that review, the agency will look at recent
safety data on triclosan, said Kweder, the deputy director of
the new drugs office. Kweder said the FDA doesn’t plan to
revisit its Total decision but that if it finds concern in its
broader review, it could look back into Total’s 1997 approval.